Method for producing 2-halogen-pyridine-carboxylic acid amides

ABSTRACT

The invention relates to a process for preparing 2-halopyridinecarboxamides of primary aromatic monoamines I which have a substituent other than hydrogen in the ortho-position to the amino group by reaction of 2-halopyridinecarbonyl chloride II with the aromatic monoamine I, which comprises carrying out the reaction in a solvent mixture comprising water and at least one water-immiscible organic solvent in the presence of none or less than 10 mol %, based on the 2-halopyridinecarbonyl chloride II, of a base other than I or II.

[0001] The present invention relates to a process for preparing2-halopyridinecarboxamides, in particular 2-halonicotinamides of primaryaromatic monoamines which have a substituent other than hydrogen in theortho-position to the amino group.

[0002] 2-Halopyridinecarboxamides of primary aromatic monoamines I whichhave a substituent other than hydrogen in the ortho-position to theamino group are known to be fungicides from EP-A 545 099. They areprepared by reacting 2-halopyridinecarbonyl chlorides withortho-substituted aromatic monoamines in the presence of a base,preferably a tertiary amine, in an organic solvent. The base serves tobind the hydrogen halide formed in the reaction and is therefore used inat least a stoichiometric quantity. A disadvantage of this is that smallbase quantities remain in the initially obtained reaction product andhave to be removed by complicated purification measures, in order toproduce on-spec fungicide. Apart from this, the use of a base is anadditional cost factor in preparing these fungicides.

[0003] There is therefore a fundamental interest in a process forpreparing these fungicides which does not require the use of a base.However, it must be taken into account that ortho-substituted aromaticmonoamines, referred to in the following as monoamines I, are stericallyhindered because of the ortho-substituent and therefore comparativelyunreactive. Additionally, the aromatic monoamines I are sufficientlybasic to be protonated by the hydrogen halide formed during thereaction, so that in the absence of a base only partial conversions aregenerally achieved. The use of stoichiometric quantities of an auxiliarybase in reacting 2-halopyridinecarbonyl chlorides II with aromatic,ortho-substituted monoamines I was accordingly hitherto regarded asnecessary.

[0004] It is an object of the present invention to provide a process forpreparing 2-halopyridinecarboxamides by reacting primary aromaticmonoamines I with 2-halopyridinecarbonyl chlorides II which delivers thedesired 2-halopyridinecarboxamides in high yield without requiring theequimolar use of a base. The process shall be especially useful for thereaction of 2-halopyridinecarbonyl chlorides with particularlyunreactive aromatic monoamines of the 2-aminobiphenyl type.Additionally, the process shall also be operable on a large scale.

[0005] We have found that this object is achieved, surprisingly, by aprocess which involves reacting 2-halopyridinecarbonyl chloride II withan aromatic monoamine I in a solvent mixture comprising water and atleast one water-immiscible organic solvent in substantial or completeabsence of an auxiliary base. The high yields achieved by this processare especially surprising because pyridinecarbonyl chlorides areexceptionally prone to hydrolysis. In general, pyridinecarbonylchlorides are therefore only converted under anhydrous conditions.

[0006] The present invention accordingly provides a process forpreparing 2-halopyridinecarboxamides of primary aromatic monoamines Iwhich have a substituent other than hydrogen in the ortho-position tothe amino group by reaction of 2-halopyridinecarbonyl chloride II withthe aromatic monoamine I, which comprises carrying out the reaction in asolvent mixture comprising water and at least one water-immiscibleorganic solvent in the presence of none or less than 10 mol %, based onthe halopyridinecarbonyl chloride II, of a base other than I or II.

[0007] For the purposes of the present invention, water-immiscibleorganic solvents include all organic solvents and solvent mixtureswhich, under the hydrochloric acid reaction conditions, form amultiphasic system comprising at least one organic and at least oneaqueous phase when mixed with water. In general, useful solvents arethose which dissolve less than 10% by volume of water or dilutehydrochloric acid. Solvent mixtures which, in addition to theabovementioned solvents, comprise water-miscible, aprotic solvents arealso useful, since these mixtures also form a biphasic system with waterunder the reaction conditions.

[0008] Examples of water-immiscible organic solvents include aromatic,aliphatic and cycloaliphatic hydrocarbons, aromatic, aliphatic andcycloaliphatic halogenated hydrocarbons, acyclic ethers preferablyhaving from 4 to 10 carbon atoms, esters having from 3 to 10 carbonatoms, preferably those of aliphatic or cycloaliphatic alcohols withpreferably aliphatic carboxylic acids, eg. esters of acetic acid,propionic acid or butyric acid with C₃-C₈-alkanols, such as methyl,ethyl, n-propyl, n-butyl or isobutyl acetate, propionate, butyrate,etc., and also ketones preferably having from 4 to 10 carbon atoms suchas methyl ethyl ketone, and also aliphatic nitriles preferably havingfrom 4 to 10 carbon atoms such as butyronitrile and also mixtures of theabovementioned organic solvents. Examples of useful water-misciblesolvents include acetone, cyclic ethers such as tetrahydrofuran,dioxane, and also acetonitrile or propionitrile.

[0009] The contents of water-miscible solvents is in general not morethan 50% by weight, preferably not more than 20% by weight, based on thetotal quantity of organic solvent. In a preferred embodiment, thesolvent used is substantially free of water-miscible solvents (content<5% by weight).

[0010] Preference is given to such organic solvents which sufficientlydissolve at least the reactants I and II. Particular preference is givento such solvents which allow reactant concentrations of at least 20% byweight and in particular at least 30% by weight to be achieved. Examplesof preferred organic solvents include aromatic, preferablyalkyl-substituted hydrocarbons such as toluene, ethylbenzene, o-, m- andp-xylene, cumene and p-methylcumene, halogenated hydrocarbons, inparticular chlorinated hydrocarbons such as dichloromethane,trichloromethane, 1,2-dichloroethane, chlorobenzene anddichlorobenzenes, ethers, for example C₂-C₄-dialkyl ethers such asdiethyl ether, diisopropyl ether, di-n-butyl ether, di-sec-butyl etherand methyl tert-butyl ether, and also cyclic ethers such astetrahydrofuran and metadioxane and the abovementioned esters havingfrom 3 to 10 carbon atoms. Mixtures of the abovementioned solvents areof course also suitable. Particularly preferred solvents and solventmixtures contain predominantly, preferably more than 80% by volume andin particular more than 90% by volume of at least one aromatichydrocarbon. Particularly preferred aromatic hydrocarbons includeC₁-C₄-monoalkyl- and C₁-C₄-dialkylbenzenes, especially xylenes.

[0011] According to the invention, the ratio of water to organicsolvents is selected so that, under the reaction conditions, a firstphase comprising the solvent and the reaction product, and also a secondaqueous phase are formed. The quantity of water is preferably selectedso that the water quantity is at least 100 g, preferably at least 200 gand in particular at least 300 g per mole of pyridinecarbonyl chlorideII. In general, not more than 1 kg of water per mole of2-halopyridinecarbonyl chloride II is used.

[0012] The quantity of water-miscible organic solvents is generallycalculated so that the volume ratio of water to solvent is in the rangefrom 10:1 to 1:10. Not least for reasons of cost, it is advantageous tokeep the quantity of solvent used as small as possible. Preference isaccordingly given to adding as much solvent as is necessary to make thetotal quantity of the reactants I and II at least 25 parts by weight,preferably at least 30 parts by weight and in particular at least 50parts by weight, based on 100 parts by weight of the organic,water-immiscible solvent. The solvent quantity will preferably be chosenso that the reactants and also the pyridinecarboxamide will be more orless completely soluble in the organic solvent under the reactionconditions, so that a substantially homogeneous organic phase can beformed. In general, at least 100 parts by weight of solvent andpreferably at least 130 parts by weight of solvent per 100 parts byweight of reactants (total quantity of I and II) will accordingly beused.

[0013] To react 2-halopyridinecarbonyl chloride II with the aromaticmonoamine I, the reactants I and II are thoroughly mixed as solutions inthe organic solvent in the presence of the desired quantity of water.This results in a spontaneous exothermic reaction with formation of the2-halopyridinecarboxamide. In general, the reaction will be carried outabove room temperature, but preferably above 40° C. and in particularabove 50° C. Preference is given to mixing together the solutions of thereactants I and II in the organic solvent in the presence of water at atemperature above 40° C. and in particular above 50° C., for example 60to 65° C., under quasi-adiabatic conditions, so that heating of thereactor contents occurs. In this case, “quasi-adiabatic conditions”refers to such reaction conditions under which the majority of theenthalpy released by the amide formation is not removed directly bycooling devices, but instead causes warming of the reactor contents.During the reaction, vigorous mixing is customarily effected by, forexample, thorough stirring and/or circulating the reactor contents bypumping. In particular, the desired quantity of water and also thesolution of the aromatic monoamine I in the desired organic solvent isinitially charged to the reaction vesssel, the reactor contents heatedto the desired temperature and then the solution of the2-halopyridinecarbonyl chloride in the organic solvent introduced withmixing into the reactor. The duration of this introduction may be from afew minutes to plural hours. The preferred quasi-adiabatic methodinvolves adding the solution of the 2-halopyridinecarbonyl chloride IIpreferably as quickly as possible, for example from 1 to 30 min, inparticular from 1 to 15 min. The concentration of the2-halopyridinecarbonyl chloride II in the organic solvent is generallyin the range from 20 parts by weight to 200 parts by weight per 100parts by weight of organic solvent.

[0014] After the addition has ended, the components are generallyallowed to react further for a period of time, preferably not more than1 h, before the workup is begun. This further reaction is preferablyeffected with mixing of the reactor contents.

[0015] The workup is effected by customary aqueous extractive methods.To this end, the aqueous phase is generally first removed from thepossibly still hot reaction mixture. The organic phase is thenneutralized, optionally after thinning with further organic solvent, byaddition of an aqueous solution of an inorganic base. Examples of usefulbases include alkali metal hydroxides such as sodium hydroxide orpotassium hydroxide, alkali metal carbonates and hydrogen carbonates andin particular sodium carbonate. The neutralization may be effected inone or more steps. The neutralization preferably involves setting a pHin the range from 6 to 10 and in particular in the range from 7 to 9.The neutralization procedure is preferably likewise effected attemperatures above 40° C., in particular above 60° C., and particularlyabove 85° C., for example in the range from 60 to 100° C. or in therange from 85 to 100° C. Preference is given to adding a hot aqueousbase solution to the hot organic phase. The neutralization may takeplace in one or more steps, and after each step, the aqueous phase isremoved from the organic phase.

[0016] The recovery of further quantities of fungicide will generally beachieved by reextracting the first aqueous phase or the combined aqueousphases with the organic solvent and neutralizing the obtained organicsolution, optionally in the above-described manner. Preference is givento returning the thus recovered re-extract to the reaction, for exampleto a subsequent batch. Of course, the fungicide may also be isolatedfrom the re-extract.

[0017] The isolation of the 2-halopyridinecarboxamide prepared in thisway from the organic phase is effected in a customary manner, forexample by concentration and/or cooling of the organic solutions andcrystallization. The crystallization may be carried out, for example, inthe presence of seed crystals.

[0018] To prepare the 2-halopyridinecarboxamide, the reactants I and IIare used in near stoichiometric quantities, ie. the molar ratio of2-halonicotinyl chloride II and aromatic amine I is in the range from0.9:1 to 1:1.1. However, preference is given to using the2-halonicotinyl chloride II in at least an equimolar quantity or in asmall excess of up to 10 mol %, preferably up to 5 mol %, based on I.

[0019] According to the invention, the process enables all primaryaromatic monoamines II which have a substituent other than hydrogen inthe ortho-position to the amino group to be converted. In principle,useful substituents are those which are inert under the given reactionconditions, ie. do not enter into competing reaction with the acidchloride function of 2-halopyridinecarbonyl chloride II. Examples ofsuch substituents include halogen, nitro, cyano, alkyl, haloalkyl,cycloalkyl, alkoxy, alkoxyalkyl, alkylthio, alkylsulfonyl, aryl,heteroaryl, arylalkyl and heteroarylalkyl. The aryl and heteroarylgroups of the last four radicals mentioned may themselves have 1, 2 or 3of the groups mentioned as substituents, for example halogen, nitro,cyano, alkyl, haloalkyl, alkoxy, alkoxyalkyl, alkylthio, alkylsulfonyl,aryl and/or cycloalkyl. In addition to the substituents in theortho-position to the amino group, the aromatic monoamine may also carryfurther, for example 1 or 2, further substituents of the abovementionedtype. Two substituents bonded to neighboring carbon atoms of thearomatic combined may also form a carbocyclic or heterocyclic 5- or6-membered ring which may itself be substituted, for example, by halogenor alkyl.

[0020] The aromatic monoamines are preferably derived from aniline.However, amines of polycyclic aromatics such as naphthylamines or aminesof benzoheterocycles may also be used as the monoamine I. The aromaticmonoamines, in particular the aniline compounds, may of course inaddition to the substituent in the ortho-position also have further, forexample 1 or 2, substituents of the abovementioned type. In a preferredembodiment of the present invention, an aniline which is onlysubstituted in the ortho-position is used.

[0021] For the purposes of the present invention, alkyl is a linear orbranched saturated hydrocarbon radical preferably having from 1 to 6 andin particular from 1 to 4 carbon atoms, such as methyl, ethyl, n-propyl,isopropyl, n-butyl, 2-butyl, isobutyl and tert-butyl. The same appliesto the alkyl moieties in alkoxy, alkythio, alkoxyalkyl andalkylsulfonyl.

[0022] For the purposes of the present invention, haloalkyl is apartially or completely halogen-, in particular fluorine-, chlorine-,bromine- or iodine-substituted, linear or branched, saturatedhydrocarbon radical having preferably from 1 to 4 carbon atoms, forexample chloromethyl, dichloromethyl, trichloromethyl, fluoromethyl,difluoromethyl, chlorodifluoromethyl, dichlorofluoromethyl,trifluoromethyl, bromomethyl, 2,2,2-trichloroethyl,2,2,2-trifluoromethyl, 2-chloroethyl, pentafluoroethyl,pentachloroethyl, 3-chloropropyl, 3-bromopropyl, etc.

[0023] Alkoxyalkyl is a linear or branched alkyl radical which issubstituted by a C₁-C₄-alkoxy group, for example methoxymethyl,ethoxymethyl, n- or i-propoxymethyl, n-butoxymethyl, 1-methoxyethyl,1-ethoxyethyl, 2-methoxyethyl, 2-ethoxyethyl, etc.

[0024] Cycloalkyl is a mono- or bicyclic hydrocarbon radical whichgenerally has from 3 to 10 carbon atoms, such as cyclopropyl,cyclopentyl, cyclohexyl, norbornyl, decalinyl or adamantyl.

[0025] Aryl is preferably phenyl or naphthyl, each of which may besubstituted by 1, 2 or 3 of the abovementioned substituents.

[0026] Heteroaryl is a heteroaromatic radical which may be mono- orbicyclic and has from 1 to 3 heteroatoms selected from O, N and S,although none of the heteroatoms may be protonatable in the aqueousphase. Examples of hetaryl are in particular thienyl, furanyl,benzothienyl, indolyl and the like. Aryl and hetaryl may be substitutedby one or more, for example 1, 2 or 3, of the abovementionedsubstituents.

[0027] In a particularly preferred embodiment of the present invention,a primary aromatic monoamine I is used which has, in the ortho-positionto the amino group, a phenyl substituent which may itself besubstituted, for example by 1, 2 or 3 of the abovementionedsubstituents. In particular, the present invention relates to a processwhere the aromatic monoamine I used is an aniline compound which has anoptionally substituted phenyl ring in the ortho-position to the aminogroup, ie. an aromatic monoamine I of the 2-aminobiphenyl type. Thephenyl ring may be substituted as described above and preferably has 1,2 or 3 of the abovementioned substituents. Particularly preferredsubstituents are selected from halogen, methyl, difluoromethyl,trifluoromethyl, methoxy, methylthio or methylsulfonyl. In a specialembodiment of the present invention, the aromatic monoamine I used is a2-(halophenyl)aniline, for example 2-(4-chlorophenyl)aniline or2-(4-fluorophenyl)aniline.

[0028] The 2-halopyridinecarbonyl chlorides used in the processaccording to the invention are preferably 2-halonicotinyl chlorides andin particular 2-chloronicotinyl chloride (=2-chloro-3-pyridinecarbonylchloride).

[0029] The process according to the invention delivers2-halopyridinecarboxamides of sterically hindered, primary aromaticmonoamines I which have a substituent other than hydrogen in theortho-position to the amino group in high yields without requiring theuse of a base. The yields from conventional workup are generally above80% of the theoretical yield. Re-extraction of the aqueous phaseregularly enables the yield to be increased above 90%. Surprisingly,only a very small quantity of 2-hydroxynicotinamide, which customarilyresults from acid hydrolysis of 2-halonicotinamides, is formed under thereaction conditions.

[0030] The present invention is illustrated by the following example:

Preparation of 2-chloro-[2-(4-chlorophenyl)phenylaminocarbonyl]pyridineby reaction of 2-chloro-3-nicotinyl chloride II with2-(4-chlorophenyl)aniline I

[0031]

[0032] A reaction vessel was charged with 800 g of water and a solutionof 396 g (1.944 mol) of 2-amino-4′-chlorobiphenyl in 311 g of xylene andheated with stirring to an internal temperature of 65° C. A solution of349 g (1.984 mol) of 2-chloro-3-nicotinyl chloride in 233 g of xylenewhich had been heated to 65° C. was then added. This resulted in atemperature increase in the reaction vessel to about 95° C. After theaddition had ended, the temperature was maintained for a further 10minutes with stirring, then the stirrer was switched off and the phasesallowed to separate. The aqueous phase was run off and collected. About360 g of hot water were added to the organic phase, which was thenstirred and a first portion of a 20% by weight aqueous sodium carbonatesolution was added. The aqueous phase was then separated off and 360 gof hot water and further 20% by weight sodium carbonate solution werethen added to the organic phase. After separating off the aqueous phase,the hot organic phase was transferred to a preheated reservoir. It wasthen cooled with stirring to room temperature and the title compoundcrystallized out. After separating off the mother liquor and drying thecrystals, 567 g of the fungicide were obtained. This corresponds to ayield of 85% based on the 2-aminobiphenyl used.

[0033] Re-extraction of the aqueous phases with xylene delivered afurther 53 g of the title compound. The total yield was 620 g (93% ofthe theoretical yield).

1. A process for preparing 2-halopyridinecarboxamides of primaryaromatic monoamines I which have a substituent other than hydrogen inthe ortho-position to the amino group by reaction of2-halopyridinecarbonyl chloride II with the aromatic monoamine I, whichcomprises carrying out the reaction in a solvent mixture comprisingwater and at least one water-immiscible organic solvent in the presenceof none or less than 10 mol %, based on the 2-halopyridinecarbonylchloride II, of a base other than I or II:
 2. A process as claimed inclaim 1, wherein the water quantity is at least 100 g per mole of2-halopyridinecarbonyl chloride II.
 3. A process as claimed in claim 1,wherein the total quantity of compounds I and II is from 25 parts byweight to 100 parts by weight, based on 100 parts by weight of organicsolvent.
 4. A process as claimed in claim 1, wherein the organic solventis selected from aromatic hydrocarbons, halogenated hydrocarbons,ethers, esters having from 3 to 10 carbon atoms and mixtures thereof. 5.A process as claimed in claim 1, wherein the reaction is carried out attemperatures above 40° C.
 6. A process as claimed in claim 1, whereinthe reaction is carried out in the absence of a base other than I or II.7. A process as claimed in claim 1, wherein the 2-halopyridinecarbonylchloride II and the aromatic amine I are reacted in a molar ratio offrom 1:1.1 to 1:1.l
 8. A process as claimed in claim 1, wherein thesubstituent in the ortho-position of the amino group in I is a phenylgroup which is itself optionally substituted.
 9. A process as claimed inclaim 8, wherein the aromatic amine I is selected from2-(halophenyl)anilines.
 10. A process as claimed in claim 1, whereincompound II is 2-chloropyridinecarbonyl chloride.